PROJECT SUMMARY/ABSTRACT Persons living with HIV (PLWH) are living longer with antiretroviral therapy (ART). Unfortunately, older PLWH also appear to be at increased risk for HIV-associated neurocognitive disorders (HAND). In parallel, as a person ages, there is risk of developing neurodegenerative disorders of late life, including Alzheimer?s disease (AD) or its precursor, amnestic mild cognitive impairment (aMCI). A current challenge lies in disentangling HAND from the more deleterious and progressive aMCI diagnosis. Distinguishing between aMCI and HAND is critical in order to provide the most appropriate life planning, intervention and treatment options for patients and to properly identify biological mechanisms of HAND. Studies that propose to identify biological mechanisms of HAND, without careful recognition that some HAND cases may either additionally have aMCI and or may have aMCI misdiagnosed as HAND, may lead to problematical mechanistic examinations of an unclear phenotype. We believe that our proposal is particularly innovative in its approach because it first attempts to clarify the phenotype of aMCI among PLWH and then examine its neurobiologic underpinnings. Participants will include PLWH who were characterized neuropsychologically in life and also have plasma, CSF, and/or neuropathologic samples available for additional characterization. Samples and data come from the National NeuroAIDS Tissue Consortium (of which the California NeuroAIDS Tissue Network at UCSD is one of four contributing banks), the UCSD HIV Neurobehavioral Research Program (HNRP) and the UCSD Shiley-Marcos Alzheimer?s Disease Research Center (ADRC). To find aMCI among PLWH, the aims use both 1) an empirically-based neuropsychological diagnostic approach, and 2) a data-driven latent class analysis (LCA) approach, which will allow us to better identify neuropsychological and biological characteristics distinguishing HAND from aMCI. Specifically, Aim 1 will use the neuropsychological diagnostic approach to identify aMCI among PLWH and compare profiles of aMCI- and HAND-associated biological markers and neurocognitive trajectories among HIV+ and HIV- diagnostic groups. Aim 2 will use a data-driven latent class analysis (LCA) approach to classify PLWH as aMCI, HAND or cognitively normal, and similarly compare profiles of aMCI- and HAND-associated biological markers and neurocognitive trajectories among LCA groups and HIV- diagnostic groups. Aim 3 will compare and validate the diagnostic and LCA classification methods. The public health benefits of our project would be significant if it is able to identify PLWH who have aMCI and reliably distinguish it from HAND. This capability would: 1) allow us to apply the approach to all PLWH to aid in identification of those at increased risk for progression to AD dementia, 2) allow for appropriate treatments to be implemented, e.g., HAND-specific treatments or aMCI/AD-specific treatments, and for these to be applied as early as possible in the course of the disease, and 3) allay fears among PLWH who do not have aMCI, a significantly more debilitating disorder that confers greater risk for dementia than HAND.